This application is submitted in response to the PA-07-173 entitled Research on Malignancies in AIDS and Acquired Immune Suppression. HIV-related diffuse large B-cell lymphoma (DLBCL) is known to be clinically more aggressive and less responsive to therapy compared to non HIV-related DLBCL. In the era of combination antiretroviral therapy (ART), HIV-related DLBCL is no longer invariably fatal and is heterogeneous in clinical outcomes. Despite the availability of potentially effective regimens for the treatment of DLBCL, more than 50% of patients continue to succumb to the disease. Therefore, understanding factors underlying HIV-related DLBCL aggressiveness and heterogeneity is critical to risk- stratified patient management and novel therapeutic development. Although clinical factors (e.g., tumor stage) are predictive for HIV-related DLBCL outcomes in the ART era, they fail to accurately predict outcome for a sizeable portion of cases and provide little therapeutic insight. Yet, knowledge on biologic factors predisposing HIV-related DLBCL prognosis is scarce. The broad objective of this study is therefore to investigate the prognostic significance of several viral and molecular factors for HIV-related DLBCL to advance clinical care and provide insight for new molecular therapeutic targets for DLBCL. The three main aims are: (1) to investigate the prognostic significance of tumor viral infection (EBV, KSHV) and several molecular agents (mutagenic molecules, cell cycle regulators, B-cell activation markers, and anti-apoptotic proteins) for HIV-related DLBCL prognosis;(2) to investigate the effect of HIV infection on viral/molecular pathogenesis in DLBCL prognosis;and (3) to build a prediction equation, incorporating both clinical factors and tumor markers, for predicting probability of disease progression for HIV-related DLBCL. The proposed study employs an observational cohort design and will include: (1) all incident HIV-related DLBCL cases diagnosed between 1996 and 2006 (expected n=192), and (2) an age- gender- and diagnosis year-matched cohort of non HIV-related DLBCL cases. Patients will be identified from Kaiser Permanente Southern and Northern California, which are integrated health care systems serving ~25% of insured Californians. Kaiser Permanente has long-standing HIV and cancer registries in addition to >80 administrative and clinical databases to perform these studies. This research will utilize archived tumor specimens available at Kaiser Permanente to assess tumor expression of selected markers via the construction of tissue microarrays and immunohistochemical staining. Patients will be followed for overall survival and disease progression through December 2009 by a standardized review of the medical records. Analytical techniques including survival analysis and logistic regression will be used to analyze data for the proposed aims. The proposed study will serve to identify tumor- related biologic factors affecting HIV-related DLBCL aggressiveness, and provide insights for novel molecular therapeutic targets. Furthermore, the study will provide a prediction equation for predicting DLBCL progression in HIV-infected patients, which will assist clinicians to evaluate both tumor characteristics and clinical factors when making therapeutic recommendations for patients. PUBLIC HEALTH RELEVANCE: This project will contribute to the understanding of tumor-related biological factors underlying the HIV- related diffuse large B-cell lymphoma aggressiveness and heterogeneity in clinical outcomes. Our results may also help to identify new molecular therapeutic targets for resistant tumor and assist with the building of an outcome prediction equation for risk-stratified patient management.